Mid-stage trial data show significant fibrosis improvement

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

The use of ASK1 inhibitor selonsertib in patients with non-alcoholic steatohepatitis (NASH) and advanced fibrosis was safe and effective.

Note that regarding selonsertib's safety, there was no significant difference between the three arms of the study in terms of adverse events.

BOSTON -- An ASK1 inhibitor called selonsertib was safe and effective in patients with non-alcoholic steatohepatitis (NASH) and advanced fibrosis, investigators said here.

In a randomized, phase II trial, patients with biopsy-confirmed NASH who received the investigational agent showed improvements in a number of measures of liver disease severity, including fibrosis stage, progression to cirrhosis, liver stiffness, and liver fat content, reported Rohit Loomba, MD, University of California at San Diego, and colleagues at the American Association for the Study of Liver Diseases annual meeting.

ASK1 (apoptosis signal-regulating kinase) promotes hepatic inflammation and fibrosis in a setting of oxidative stress, which plays an important role in the progression of NASH, Loomba pointed out. Selonsertib (GS-4997) is an oral small molecule ASK1 inhibitor that has been shown in mouse models to improve steatosis, inflammation, and fibrosis.

"The aim of this study was to evaluate the safety and efficacy of GS-4997 in subjects with biopsy proven NASH and stage 2 and 3 fibrosis," Loomba said.

For the study, 72 patients were randomized, and in the 24 weeks after liver biopsy, they received either 6 or 18 mg of selonsertib orally alone, or in combination with simtuzumab (125 mg weekly). Another group of patients received simtuzumab alone.

Liver biopsies were performed at baseline and at 24 weeks, while hepatic proton density fat fraction was measured by MRI, and liver stiffness by MR elastography (MRE) at baseline, 12 weeks, and 24 weeks. Liver fat content was measured by proton density fat fraction MRI (MRI-PDFF).

Since Loomba and his colleagues observed no differences between combination and monotherapy, for purposes of presenting data they divided the study participants into three groups:

18 mg of selonsertib alone

18 mg of selonsertib plus simtuzumab

6 mg of selonsertib alone

6 mg of selonsertib plus simtuzumab

125 mg simtuzumab alone

The authors found that after 24 weeks, the 18 mg selonsertib plus simtuzumab and the 6 mg selonsertib plus simtuzumab groups achieved 43% and 30% fibrosis improvement rates, respectively, compared with the 125 mg simtuzumab alone, which only achieved a 20% improvement rate

Loomba reported that results were similar when his group examined fibrosis improvement rates that occurred without NASH worsening.

"Conversely, if things are improving, there should be some reduction in terms of progression of fibrosis as well," Loomba said. "And we are seeing that." Specifically, just 5.3% of the patients who took selonsertib with simtuzumab experienced fibrosis progression versus 20% of patients who took simtuzumab alone.

The authors also reported that 26% and 13% of the 18 mg selonsertib plus simtuzumab and 6 mg selonsertib plus simtuzumab groups respectively achieved a ≥30% reduction in liver fat, compared with just 10% of the simtuzumab alone group.

"So these are big reductions in liver fat," Loomba said. "For example, if your patient started at 20% liver fat at baseline, they were down to 14% or less."

Loomb's also found fibrosis responders in the selonsertib plus simtuzumab groups achieved significant reductions in ALT levels. "And there were dramatic reductions in CK-18 levels (in both M30 and M65 fragments) in the 18 mg and 6 mg dose," Loomba added.

As for the agent's safety, there was no significant difference between the three arms of the study regarding adverse events. There was one serious related adverse event in the 18 mg selonsertib plus simtuzumab, and three patients discontinued treatment in the selonsertib groups due to an adverse event.

"GS-4997 has beneficial effects on fibrosis regression, as well as reduced progression to cirrhosis," Loomba concluded. "Liver stiffness by MRE had some improvement in the 18 and 6 mg groups, and there were improvements in MRI-PDFF, as well as ALT and CK-18 levels. GS-4997 was also thought to be safe and well tolerated."

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